Updated: May 30
Informative Abstract:
Key Terms:
Biologics - medicines that are protein-based antibodies developed through genetic engineering.
Colectomy - surgical removal of a part of the colon or all of its parts.
Crohn’s disease - chronic inflammatory disease of the bowel that may affect any portion of the gastrointestinal tract from mouth to anus but it mostly afffects the small intestine and colon.
TNFα - Tumour necrosis factor alpha. A cytokine produced by macrophages as a result of the immune system response leading to the further release of other chemical mediators.
Ulcerative colitis - chronic inflammatory disease of the bowel that only affects the large bowel.
Background:
Infliximab is just one of the many drugs used in the treatment of inflammatory bowel disease (IBD). It is a monoclonal antibody used in decreasing the inflammation of the bowel wall from IBD. There are two major types that come under this disease: Chron’s disease and ulcerative colitis. Though similar because of their clinical feature, both are different in some ways as to what part of the bowel they afffect. Chron’s disease affects various parts of the digestive tract in which inflammation can appear from the mouth, the intestines and up to the anus and vice versa whereas ulcerative colitis only affects the large bowel including the sigmoid colon and the rectum (Whayman, 2011).
The action of infliximab is basically in the inhibition of an inflammatory cell signalling protein or cytokine known as the tumour necrosis factor alpha (TNFα). The cause of inflammatory bowel disease is still unknown. Various factors are associated with the development of IBD however the role of TNFα in IBD has been highly contributory (Satsangi and Sutherland, 2003). Clinical studies in the use of infliximab among patients has resulted to a favourable percentage of remissions among patients. The availability of infliximab in the market as a licensed drug for IBD is recent and its use has been enormously costly that is why health practitioners involved in the care of patients with IBD carefully assess the necessity of the drug along with its pros and cons also taken into account . Though a lot of patients have already benefited with the drug in clinic visits, some evidence also show that it also exhibits certain adverse effects.
This purpose of this blog post is to review the effects of infliximab in inflammatory bowel disease focusing on how it inhibits TNFα. Some clinical studies will also be reviewed to explore the mechanisms of IBD with some focus on the role of TNFα as well as the significant outcomes of the clinical trials done with infliximab therapy and also the safety issues related to its administration.
The Discovery of Infliximab
The use of biologics such as infliximab has been used in immune related diseases such as rheumatoid arthritis. Its use in the treatment of IBD is also recent. Infliximab was developed by Junming Le. His main area of expertise was on monoclonal antibody technology and this was worked together with Jan Vilcek who was a pioneer in the studies of soluble mediators that regulate the immune system which includes tumour necrosis factor alpha. With the collaboration of Centocor, a biotechnology company, infliximab was developed with the name 'Remicade' (NYU Langone Medical Center, 2005).
In 1998, infliximab first came into market and was approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (Nordqvist 2014). It is the first anti-TNF antibody approved for rheumatoid arthritis and also in the same year for the treatment of moderate chron’s disease (Bartfai & Lees 2013).
Clinical Studies of infliximab in inflammatory bowel diseases
Several studies revealed favourable results in the use of infliximab among IBD patients. In a study called ACCENT 1 which is a randomized control 54-week trial on determining the benefits of infliximab as maintenance therapy among patients with crohn’s disease who had responded to a single infusion of the drug, their findings revealed that the two groups (both groups given different doses) who have received further doses of infliximab in several visits timed in several weeks had shown to be more likely to sustain clinical remmissions than on the other group who was only given a placebo (Hanauer et al, 2002).
In a retrospective data analysis study on patients with Chron’s disease in relation to the effectiveness and tolerability of repeated treatment with infliximab, it has been shown that following the treatment with the drug, steroids taken by patients could be withdrawn in 47% of the patients and the tolerability and efficacy of infliximab among patients were judged to be very good or good among physicians as this study was done under routine conditions and private practices. The study concluded that in a majority of patients with fistulating and refractory chron’s disease, individually adapted regimen use of infliximab has induced a significant clinical response in which near 80% of the patient’s steroids could be withdrawn (Witthoft & Ludwig 2005).
Studies on infliximab use in ulcerative colitis also showed significant findings. In a review study of infliximab use in ulcerative colitis, the use of infliximab was associated with a significant reduction in the need for colectomy as compared with the placebo group in a multicentre double-blind placebo controlled study in 45 patients. The review has then suggested that among patients with moderate to severe ulcerative colitis with an inadequate response to steroid therapy such as glucocorticoids, infliximab is an effective alternative treatment (Wilhelm et al, 2008). In another study, which was a randomized, double-blind, placebo controlled study on the induction and maintenance infliximab therapy for ulcerative colitis, among the 364 patients with moderate to severe UC, those who received treatment with infliximab at weeks 8, 30, and 54 in their study had shown to have a clinical response as to those who were only receiving a placebo (Rutgeers et al 2005).
The bowel wall & the mucosal immune system
Though in Chron’s disease the affected parts include other gastrointestinal areas such as the mouth and the esophagus, inflammation of the small intestine, the colon, rectum and anus are also common. These parts form the bowel, the parts that are below the stomach. The function of the bowel is to absorb nutrients and fluids so that the body can use it up for energy and water replenishment. This is made possible due to the complex structures of the bowel wall which is composed of several layers. The bowel is a hallow organ. The small intestine is where most food digestion and nutrient absorption takes place. The internal walls of the small intestine have finger-like projection structures called villi wherein most of the absorption takes place. Further into the internal layers of the human gut is the lamina propria which contains blood vessels. The lamina propria of the bowel wall houses a large number of immune cells wherein the mucosal immune system is associated.
The mucosal immune system responds when there is invasion in the tissues & cells such as the presence of certain bacteria or viruses. The activated response will result in various processes that can lead to inflammation. This process occurs as a result of the release of certain chemical mediators. The chemical mediators are released because of antigenic stimulation. In IBD, the common cytokine profiles of inflammation include the T cell subset 1 (Th1) cytokine, and the T cell subset 2 (Th2) type. Under the Th1 cytokine subset are the interferon-y (IFN-y), tumour necrosis factor (TNF), interlukin 12 (IL-12) and interlukin 2 (IL-2) while the Th2 cytokines include interlukin 4 (IL4), IL-5, IL-6 and IL-10 (Whayman et al, 2011).
The cell-mediated immune cytokine expression response is thought to be mostly associated in chron’s disease whereas ulcerative colitis is in the humoral immune response. Although the inflammation in chron’s may also appear from humoral immune response activation, cytokine expression from cell-mediated immunity is common (Sands & Kaplan, 2007). In inflammatory bowel disease, there is chronic inflammation because of an imbalance in the immune system response. According to Cotran et al 1999, there is failure in the down- regulation of the immune system which may be due to inappropriate exposure to luminal antigens.
There are two major phases in the cellular and humoral immune response. These are the activation and effector phases. The cell mediated immunity is activated when an antigen presenting cell attacks an invader such as that of a virus. At the same time, other viruses will also attack and infect other cells nearby such as epithelial cells. The antigen presenting cell such as the macrophage engulfs the virus to process the antigens through phagocytosis. The antigens will combine with MHC class II proteins and will be presented in the surface of the antigen presenting cells. These antigens in the surface of the presenting cell is called the MHC class II-antigenic peptide complex. The virus that infected the epithelial cells will also be processed by lysosomes and it will be attached to the MHC class I protein and be presented on the surface of the cell which will then be called the MHC class I-antigenic peptide complex. The helper T cells will recognize this antigen displayed in the antigen presenting cell and thus the helper T cell binds to the MHC class II-antigenic complex. This will activate the helper T-cell which stimulates the release of cytokines such as IL-2 and IFNy. The effector phase starts when a cytotoxic T cell that was stimulated by the chemical mediators previously released will recognize and bind to the MHC class-I antigen peptide complex on the epithelial cells infected by the virus. As a result, the cytotoxic T cell will then release perforin which functions to perforate the cell membrane of the infected cell leading to cell apoptosis. Once the infection is in control, the inactive cyctotxic T cells will be deactivated by the regular T cells (Roitt et al, 2001).
In the humoral immune response, the process of immunity is activated when a bacteria is being engulfed by the antigen presenting cell wherein lysozymes from within the cell digest the bacteria to process the antigen. The antigen binds with MHC class II protein and the antigen is presented into the surface of the antigen presenting cell called the MHC class II-antigenic peptide complex. The helper T cells (CD4+) recognizes this and binds, thus triggering the release of certain chemical mediators such as the IL-2 which then stimulates the activated helper T cells to proliferate into many helper T cells with receptors that are specific for the antigen that was previously processed. When a B cell that has a receptor specific for that antigen engulfs a bacteria, the effector phase begins. The bacteria is phagocytosed and the antigen is processed by binding to MHC class II protein and is then presented into the surface of the B cell. The helper T cells bind to this antigen causing the release of certain cytokines which stimulates the B cells to proliferate. These B cells then differentiate into memory B cells which release antibodies that can fight against the bacteria through a lock and key fashion, thus can directly lyse the bacteria. Simultaneously, the blood complement system also assists in the immune process response (Roitt et al, 2001).
T cell activation in immune resonse. Source: The University of Illinois ad Chicago, n.d.)
The inflammatory processes present in IBD appears as chronic since the sensing of the immune system is deregulated. It should also be noted that IBD has periods of remission and exacerbation and these exacerbations occur as a result of the immune system mechanism in which the chemical mediators play a role in the resulting inflammations in the bowel walls as well as the actions of the activated T cells (Satsangi and Sutherland 2003).
The Role of Tumour Necrosis Factor alpha (TNFα) in the development of inflammatory bowel diseases
Tumour necrosis factor alpha is a proinflammatory cytokine which is mainly produced by activated macrophage and T-lymphocytes as a result of an immune system response. It has a significant role in amplifying the inflammatory reactions through an increase in the regulation of adhesion molecules resulting in the local recruitment of lymphocytes and the activation of other pro-inflammatory cytokines and matrix metalloproteinase induction in the lamina propria . TNFα is seen to also have a role in the inflammatory conditions other than inflammatory bowel disease such as spondylarthropathy, psoriasis and rheumatoid arthritis (Armuzzi et al, 2008).
When the activated T lymphocytes and macrophages produce TNFα, this will activate the leukocytes to induce metalloproteinases and induce acute phase reactants which leads to the enhancement of leukocyte migration. TNFα also induces the release of other pro-inflammatory cytokines such as IL-1 and IL-6 while at the same time it also inhibits the apoptosis of inflammatory cells. TNFα is found to be in high amounts in the lamina propria of patients with inflammatory bowel disease thus explains the connection of TNFα as one of the precipitating factors in the development of IBD. It is because of this inability of the body to down regulate the immune system that results in the chronic inflammation in IBD. The TNFα stimulates the ongoing process of releasing various chemical mediators even when there is no significant infection going on (Poggioli et al, 2007).
Pathway of mucosal inflammmation in IBD
from TNFα. (Source: Nature Reviews: Immunology, 2003)
TNFα has various biological effects. Aside from inflammation that is frequently mentioned as a result of the pro-inflammatory cytokines produced by activated macrophages, the increase in adhesion molecules that it promotes also leads to cell infiltration and neutrophil recruitment. In addition, tissue remodelling also occurs due to metalloproteinase and collagen synthesis and it also impairs the barrier function in the epithelium as a result of increased permeability (Sands and Kaplan, 2007). Evidence of TNFα is greatly increased in patients with inflammatory bowel disease from mucosal biopsies and an increased concentration of TNF has also been found in stool samples of patients during the exacerbation of the disease (Poggioli et al, 2007). The role of TNFα is widely important in the pharmacologic studies of infliximab. TNFα is the primary cytokine that infliximab inhibits thus reducing the onset of exacerbation of the disease thus maintaining the bowel in a dormant phase against being chronically inflammed.
Inflammatory Bowel Disease Pathophysiology
There are two major diseases that come under inflammatory bowel disease. Chron’s and ulcerative colitis may be the same in a way that it causes inflammation of the bowel wall however they are different in other ways. The causative factor of IBD is still unknown however some factors are thought to predispose a person to develop it. A few of these is genetics, the alteration of the immune response, microbes, stress, and the environment (smoking, hormonal contracepcions, isotretinoin and etc).
Familial aggregations have been observed in IBD however a clear mendelian evidence has not been evident. Mutations in the nucleotide-binding oligomerization domain -containing protein 2 (NOD2) gene, also knnown as IBD1, has been associated with the development of Chron’s disease (Philpott et al, 2014). NOD2 has a gene location in chromosome 16 (Whayman 2011). The normal role of NOD2 is that it senses the peptidoglycan of microbes which derives a physiological inflammatory response through the kinase receptor-interacting protein 2 which leads to the activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB). The NF-kB mediated gene transcription will stimulate the production of antimicroial peptides and mucins increasing the barrier immunosurveillance of the intestinal walls. The NF-kB activation does this because the process stimulates the T-helper cells to produce interlukin-22 and regenerating the islet-deprived protein IIIy (REGIIIy) and in addition it also stimulates the monocytes to enhance barrier surveillance thru CC-chemokine ligand 2 (CCL2) resulting in the mediated recruitment of Ly6Chigh monocyte response. What happens in chron’s disease is that the defective NOD2 has lost petidoglycan sensing which explains the chronic inflammation that occurs as a result of the cascade of events that it follows (Philpott et al, 2014).
Together with the combination of various predisposing factors involved is the impairement in the innate immunity in which an overactive Th1 and Th2 cytokine response results and the T cells infiltrate the gastrointestinal wall leading to the inflammation of the large intestine for ulcerative colitis and inflammation of various parts of the gastrointestinal tract in Chron’s disease. The difference in Chron’s disease and ulcerative colitis in clinical pathology is that ulcerative colitis only appears in the large intestine, rectum and anus whereas in Chron’s, it can appear anywhere in the gastrointestinal tract from mouth to anus and the inflammmation may be patchy as well as transmural (Whayman et al, 2011).
Some microbes such as an adherent-invasive eschericia coli induce an increase in the secretion of TNFα. The bacteria tend to make strong biofilms which stimulate the release of TNFα leading to sustained microbial-induced inflammation resulting to the inflammation of the colon in chron’s disease. It can also be noted in ulcerative colitis that an increase in the colonic sulfate-reducing bacteria leads to the interruption of the acetyl CoA dehydrogenase which is an enzyme in the beta oxidation pathway. This is due to the increase in the concentration of hydrogen sulfide from the colonic sulfate-reducing bacteria thus results to an impairment in the beta oxidation pathway and inflammation of the lining of the bowel.
Pharmacology of Infliximab
Infliximab is a genetically engineered immunoglobulin I which is composed of a 75% human constant and a 25% murine variable region (Armuzzi et al, 2007). It is a murine-human chimeric monocloonal antibody and the murine part is the side that is capable of binding to human TNF whereas the human tract functions to preserve the functional immune capacity and decreasing immunogenicity (Poggioli, 2007). Infliximab has been used as a rescue therapy in ulcerative colitis (Longmore et al, 2007) and it is also indicated for use in refractory luminal Chron’s disease as well as the steroid-dependent and refractory fistulizing chron’s disease ((Poggioli et al, 2007).
Infliximab is initially administered at 5 mg/kg at weeks 0, 2, and 6 via the intravenous route and the therapy has been shown to be effective in inducing remissions among patients with moderate to severe ulceratuve colitis.. The infusion therapy is maintained every 8 weeks however it shouldn’t be used for people who have high risks for infection since the drug can also make a person susceptible to infections to some extent (Whayman et al, 2011).
The mechanism of action of infliximab is geared towards inhibiting TNFα. Infliximab neutralizes TNFα thru binding with the soluble and transmembrane forms of TNFα. The murine portion of the infliximab structure has a high affinity towards TNFα thus the drug will inhibit the binding of TNFα with its receptors capably inhibiting the inflammatory processes that it succeedingly brings. Research has also shown that infliximab has other functions which include the modulation of the cells that produce TNF through a process called complement fixation, antibody-dependent cytotoxicity toxicity and apoptosis of the monocytes and T lymphocytes, and the down regulation of other chemical mediators (Poggioli et al, 2007).
The effects of infliximab in inflammmatory bowel disease has been evidenced by several research studies. It targets not only the soluble TNF but also the T cells in the lamina propria, peripheral blood T cells and mononuclear cells and other targets affected by inflammatory bowel disease. Infliximab has been known to induce apoptosis of the lamina propria T cells by binding to tmTNE thus inducing certain caspases such as the caspase 3, and caspase 8, as well as the Bax and Bak. Caspases are essential in cells for apoptosis as well as the Bax and Bak when activated. Infliximab has also shown to decrease the production of proinflammatory chemical mediators in the Jurkat T cells. Furthermore, the drug decreases the expression of CD40 and VCAM-1 on intestinal vasculature, and it also restores the colonic epithelial barrier thus increasing resistance by decreasing the number of the apoptotic cells.
Infliximab has a chemical formula of C6428-H9912-N1694-O1987-S46 (drugs.com, 2015). As mentioned earlier that it is a murine-human chimeric monoclonal antibody, the murine portion is less than half of its total size. Both its murine and human sides have binding sites specific for TNF however the murine side is mmost likely to bind to the TNF alpha type.
Structure of infliximab.
(Source: Indian Journal of Dermatology, Venereology and Leprology, 2013)
Safety in the use of infliximab
The body’s immune system is a line of defense against microbes and viruses. The release of tumour necrosis factor alpha in the cascade of events that follow an immune response is a defense mechanism against infection. Though therapuetic administration of infliximab have exhibited a number of positive results among research studies, its use must also be applied with great caution. It should be noted that when TNFα is inhibited to proceed with its role in the immune system as a result of the mechanism of action of infliximab, the patient is at risk for infection as well as superinfecction. In fact, one of the screenings performed for patients who are to receive infliximab is that they should not be positive for tuberculosis infection. The use of infliximab should be weighed against its benefits and the adverse effects, and proper assessment should be necessary before the use of the drug is commenced.
Conclusion
Infliximab therapy has shown a number of positive outcomes among patients with inflammatory bowel disease. There are several factors that precipitate a person to develop IBD and thus it should also be noted that the medical management of the disease is done with thorough evaluation of the right drug. It can be gleaned from the several clinical trials of infliximab that not all patients exhibit remissions as a result of its therapy and there is also that percentage of the population that do not respond to the drug at all. Thus it should also be considered that in treating inflammatory bowel disease, the exact cause is still unknown.
It is also noteworthy to dictate that the development of infliximab did a significant contribution in the treatment of IBD. It is still not going to be the cure as patients will still exhibit symptoms associated to the periods of exacerbation and remission. Finding the cure for IBD is still an ongoing area of research. The development of new drugs such as infliximab as well as discovering the role of tumour necrosis factor alpha in IBD have all brought significant contributions in the management of the disease.
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